Methods

Study design and population

We performed a single-center prospective cohort study enrolling adults age 60 years or older newly diagnosed with AML between November 2016 and December 2019 who underwent intensive induction chemotherapy. Inclusion criteria were as follows: newly diagnosed AML, age between 60 and 75 years, Eastern Cooperative Oncology Group performance score (ECOG PS) ≤2, plan for intensive induction chemotherapy, and ability to provide written informed consent and answer various questionnaires. Exclusion criteria were the presence of another active malignancy, acute promyelocytic leukemia, AML involving the central nervous system, active infection or uncontrolled bleeding, or impaired organ function such as severe renal, hepatic, or cardiac dysfunction. All patients received induction chemotherapy consisting of idarubicin (12 mg/m²) for 3 days plus cytarabine (100 mg/m²) for 7 days.^[17] Sixty-one patients (58%) underwent allogeneic stem cell transplantation with suitable donors after 1 or 2 cycles of consolidation.^[17] The Institutional Review Board of The Catholic Medical Center approved this study. All analyses were performed according to the Institutional Review Board guidelines and the tenets of the Declaration of Helsinki.

GA measures

GAs were performed in the inpatient ward at enrollment by a study nurse who followed published procedures for administration and scoring of each assessment. We performed objective physical performance measurements of handgrip strength and the Short Physical Performance Battery (SPPB). Handgrip strength (in kilograms) was measured by using a hydraulic grip strength dynamometer and was performed by a professional rehabilitation medicine doctor.^[18] SPPB reliably predicts future disability, hospitalizations, and mortalities among elderly patients, consisting of a gait speed test (distance of 4 meters), sit-and-stand speed test (standing from a chair maneuvers repeated 5 times), and balance tests (subdivided into side-by-side stand, semi-tandem stand, and tandem stand balancing for 10 seconds each); each measurement was scored from 0 to 4 (0 is unable to complete the test and 4 is the highest performance level), with a total score ranging from 0 to 12.^[19] SPPB, gait speed, and sit-and-stand speed were analyzed as categorical variables using cutoffs of ≤8, ≤3, and ≤3, respectively, for impairment. Cognitive function was assessed using the Mini-Mental State Examination in the Korean version of the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) Assessment Packet (MMSE-KC), which has been used widely and validated in the Korean population to measure cognitive impairment.^[20] MMSE-KC comprehensively evaluates different subsets of cognitive status, including attention, language, memory, orientation, and visuospatial proficiency. We also used the Korean version of the Nursing Delirium Symptom Checklist (KNU-DESC), a recently developed accurate but straightforward and sensitive screening instrument for detecting cognitive impairment, especially early delirium. KNU-DSEC consists of 5 categories of assessment: disorientation, inappropriate behavior, inappropriate communication, illusions or hallucinations, and psychomotor retardation.^[21] For psychological function, we used 2 scales of the Korean version of the Short-Form Geriatric Depression Scale (SGDS-K), which focuses on depressive symptoms in elderly populations, and Patient Health Questionnaire-9 (PHQ-9), more generalized screening tools of depression and related psychologic diagnoses.^[22,23] In addition, we used the National Comprehensive Cancer Network’s Distress Thermometer (NCCN-DT) screening measure to identify and address psychological distress.^[24] Social support was assessed by using Older Americans Resources and Services (OARS), and nutritional support was evaluated with the Mini Nutritional Assessment (MNA).^[25,26] Nutritional support and bedside or ambulatory physical training programs were provided by expert therapists based on referral. Psychiatrists were involved in treatment only when referred for psychological symptoms. Cutoff values for other categorical variables were as follows: MMSE-KC (≤23), KNU-DESC (≥2), SGDS-K (≥6), PHQ-9 (≥6), NCCN-DT (≥3), OARS (≥18), and MNA (≥23.5).

Covariates

Patient-specific variables (echocardiogram, pulmonary function test, and body temperature) and AML-specific variables (white blood cell count, platelet count, lactate dehydrogenase level, previous myelodysplastic syndrome or history of other malignancies, cytogenetic abnormalities, and genetic mutations screened by real time-quantitative polymerase chain reaction or next-generation sequencing panel customized for acute leukemia^[27]) were collected from medical records. The attending physician’s estimate of ECOG PS at admission was recorded and categorized as good functional status (score ≤1) or poor functional status (score >1). Comorbidity burden was scored using the Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI).^[28] Those variables were used to categorize patients using preexisting survival prediction models: AML scores,^[14] Ferrara criteria,^[15] Wheatley index,^[16] and European LeukemiaNet 2017 (ELN 2017) risk classification.^[29]

Outcomes and definitions

The primary outcome was overall survival (OS) defined as the date of diagnosis to the date of death or last follow-up for censored patients. The secondary outcomes were ED,^[12] defined as death within 60 days after induction chemotherapy, complete remission (CR), and nonrelapse mortality (NRM). We defined CR as a morphologic leukemia-free state with <5% blasts in the bone marrow and no persistent extramedullary disease. NRM was empirically defined as death for any reason without evidence of disease recurrence and was calculated by cumulative incidence estimation, treating relapse as a competing risk. The adverse events were evaluated by the National Cancer Institute’s Common Terminology Criteria for Adverse Events (version 4.0), in which nonfatal toxicities were grades 1 to 4, and fatal toxicity was grade 5.

Statistical analysis

The categorical variables were compared using a χ^[2] analysis and Fisher’s exact test, and continuous variables were assessed using Student t test and the Wilcoxon rank-sum test. OS was estimated using Kaplan-Meier analysis, and the difference in survival between the groups was compared using a log-rank analysis. NRM was assessed using a cumulative incidence estimation method, and comparisons of NRM between the groups were based on Gray’s competing risk method. Multivariable logistic regression was used to examine baseline GA measurements as predictors of adverse events during induction chemotherapy, including infection, acute renal failure, hepatotoxicity, gastrointestinal complications, and prolonged hospitalization longer than 40 days. We also examined survival (OS and NRM) predictors by comparing available clinical variables such as baseline characteristics, GA measurements, and preexisting survival prediction models. Variables found to be significant in univariable models were included in multivariable models. Highly correlated variables were evaluated by the correlation coefficient of each predictor. We designed separate multivariable models for highly correlated variables. Multivariable models were derived using stepwise selection among candidate variables with the Wald test for overall P value for factors with >2 levels and a value of P < .05 to warrant inclusion in the model. To assess the incremental impact of score variables on predicting survival, we used Integrated Discrimination Improvement (IDI) as described for survival analysis by Chambless et al.^[30] Statistical significance was determined as a P < .05 (2-tailed). All statistical analyses were conducted using SPSS, version 13.0 (SPSS, Chicago, IL) and R software (version 3.4.1; R Foundation for Statistical Computing, 2017).